title: Inhibiting cardiac allograft rejection with interleukin-35 therapy combined with decitabine treatment in mice.
abstract: BACKGROUND
  Regulatory T (Treg) cells play a pivotal role in the maintenance of transplantation tolerance. It is of great interest to induce allograft tolerance mediated by regulatory CD4(+)CD25(+) T cells.
  
  
  METHODS
  Here we investigated the effect of hydrodynamic IL-35-expressing plasmid injection in combination with a methyltransferase inhibitor (decitabine) on immune function and transplantation tolerance in mice.
  
  
  RESULTS
  We showed that IL-35 and decitabine stimulated the proliferation of CD4(+)CD25(+) Tregs and suppressed CD8(+) T cell proliferation in an allogenic mixed lymphocyte culture in vitro. IL-35 gene therapy and decitabine administration prolonged the survival of the transplanted heart in the heterotopic abdominal heart transplantation model in mice.
  
  
  CONCLUSIONS
  The possible mechanism through which IL-35 and decitabine treatment increased the survival of graft tissues is to enhance the proliferation of CD4(+)CD25(+) Treg cells and suppress the generation and function of effector T cells. Thus, IL-35 gene therapy combined with decitabine provides a novel approach to induce transplantation tolerance.
authors.affiliation: Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin General Surgery Institute, Tianjin Medical University General Hospital, Tianjin 300052, China. Electronic address: guohaoay@163.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.forename: Xianghui
authors.initials: X
authors.lastname: He
authors.forename: Liwei
authors.initials: L
authors.lastname: Zhu
authors.forename: Xueming
authors.initials: X
authors.lastname: Jiang
mesh_terms: D064591:Allografts; D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015316:Genetic Therapy; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D057809:HEK293 Cells; D016027:Heart Transplantation; D006801:Humans; D007378:Interleukins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids / Q000276:immunology / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D023001:Transplantation Tolerance
chemical_list: D004791:Enzyme Inhibitors; D007378:Interleukins; C569375:interleukin-35, mouse; D000077209:Decitabine; D001374:Azacitidine
keywords: 5-Aza-2′-deoxycytidine; Aza; CD4(+)CD25(+) Treg cell; Cardiac allograft; DNA methyltransferase; DNMT; Decitabine; FCM; Flow cytometry; IL-35; MLR; Mixed leukocyte reaction; Regulatory T cells; Treg